From the Cardiovascular Health Research Unit (W.T.L., D.S.S., S.M.S.,
B.M.P., T.E.R., T.D.K.) and the Departments of Neurology (W.T.L.),
Epidemiology (W.T.L., D.S.S., S.M.S., B.M.P., T.D.K.), Medicine (D.S.S.,
B.M.P., T.D.K.), Health Services (B.M.P., T.D.K.), and Biostatistics (T.E.R.),
University of Washington, Seattle, Wash; the Hemostasis and Thrombosis
Research Centre (F.R.R., H.L.V., P.H.R.) and Department of Clinical
Epidemiology (F.R.R.), University Hospital Leiden, Leiden, the Netherlands;
and the Laboratory for Experimental Internal Medicine, Academic Medical
Center, University of Amsterdam (The Netherlands) (P.H.R.).
Correspondence to W.T. Longstreth, Jr, MD, Department of Neurology, Box 359775, Harborview Medical Center, 325 Ninth Ave, Seattle, WA 98104-2499. E-mail wl{at}u.washington.edu
Methods—We conducted a case-control study in western Washington
state. Case patients were women aged 18 to 44 years with a first stroke
(n=106). Control subjects were women without stroke recruited from the
same region by use of random-digit telephone dialing (n=391). All were
interviewed and provided blood specimens, which were genotyped
for these mutations.
Results—Factor V Leiden was found in 0.9% of case patients, a
single patient with a subarachnoid hemorrhage, and in
4.1% of control subjects. The odds ratio (OR) for any stroke was 0.2
(95% confidence interval [CI], 0.03 to 1.7). The prothrombin variant
was found in 1.9% of case patients, 1 with a venous stroke and 1 with
an ischemic stroke, and in 1.6% of control subjects. The OR
for any stroke was 1.48 (95% CI, 0.14 to 9.17). ORs for stroke types
were also not statistically significant.
Conclusions—In this study, neither factor V Leiden nor the
prothrombin variant (G20210A) was an important risk factor for stroke
in young women. In this setting, screening for these mutations cannot
be recommended. Unanswered by this study is whether screening would be
useful in select patients, such as those with a strong family history
of thrombophilia or those with venous strokes.
Study personnel abstracted diagnostic information from
hospital records. Results of brain imaging studies were available
for 92% of the case patients. The study neurologist (W.T.L.) reviewed
the hospital records of all potential case patients to confirm the
diagnosis and to classify the type of stroke. We identified 249
eligible case patients through the review of discharge diagnoses from
all hospitals within the study region; 198 were living at the time we
initiated recruitment activities, and 149 were recruited and
interviewed.
We used random-digit telephone dialing to identify a sample of women
aged 18 to 44 years who were residents of King, Pierce, or Snohomish
county during the time period of the study, as described
previously.35 Control subjects were frequency
matched to case patients by age. Of the 684 eligible women, 526 were
recruited and interviewed.
Participating case patients and control subjects were interviewed in
person regarding cardiovascular and cerebrovascular
risk factors. In addition, the interviewer obtained 30 mL nonfasting
venous blood in EDTA-treated evacuated tubes from the antecubital vein.
Samples were collected from 106 of 149 participating case patients
(71%) and 391 of 526 participating control subjects (74%) who were
interviewed. We compared the women who were interviewed and gave blood
with those who were interviewed but declined venipuncture
and found no important differences (data not shown). Blood specimens
were genotyped for factor V Leiden and the prothrombin variant
with use of published methods.5 6 Briefly, the
presence of factor V mutation (1691, G-to-A replacement) was inferred
from the loss of an Mnl I restriction
site5 and the presence of the prothrombin variant
(20210, G-to-A replacement) was confirmed by the presence of a
HindIII restriction site in an A allele–specific
polymerase chain reaction fragment.6 These
determinations were accomplished without knowledge of whether the
specimen came from a case patient or control subject. Determinations
for factor V Leiden were available in 105 of the 106 case patients
(99%) and 388 of the 391 control subjects (99%) and for the
prothrombin variant in 105 case patients (99%) and 382 control
subjects (98%). Altogether, genotyping for both mutations were
available in 381 control subjects (97%) and 104 case subjects
(98%).
The association of these two mutations with stroke was examined by the
calculation of the odds ratio (OR), as an estimate of relative risk,
and 95% confidence interval (CI).36 The study
was approved by the Human Subjects Review Committee at the University
of Washington, and those who participated in the study all provided
informed consent.
Six of the 382 control subjects (1.6%) and 2 of the 105 case patients
(1.9%) had the prothrombin variant. One, a 33-year-old white woman who
was using oral contraceptives at the time of her event, was free of
other recognized stroke risk factors and had a venous stroke. The other
was a 32-year old white woman with long-standing hypertension and
epilepsy who had an ischemic stroke 11 days postpartum.
Evaluation failed to suggest a right-to-left shunt through the heart,
and venous thrombosis of the lower extremities was not clinically
evident. The OR for any stroke was 1.2 (95% CI, 0.1 to 6.9); for
hemorrhagic stroke, 0 (95% CI, 0.0 to 6.8); and for ischemic
stroke, 1.6 (95% CI, 0.03 to 13.4). Again, these CIs are broad and
include 1.
Carriership of either mutation was found in 22 of 382 control subjects
(5.8%) and 3 of 104 case patients (2.9%). The OR for any stroke was
0.49 (95% CI, 0.09 to 1.7). No one carried both mutations, although 1
control subject who had factor V Leiden and who was included among the
22 control subjects above could not be genotyped for the
prothrombin variant. None of the 3 case patients with one of these
mutations had a family history of stroke, and the only case patient
with the factor V Leiden (who suffered a subarachnoid
hemorrhage) had a family history of myocardial infarction. This
patient's brother was reported to have suffered a myocardial
infarction at age 27 years. Of the 22 control subjects with either of
the mutations, 3 (13.6%) had a family history of stroke, 7 (31.8%)
had a family history of myocardial infarction, and 10 (45.4%) had a
family history of either stroke or myocardial infarction.
We had only two women with venous strokes in the current study. Neither
had factor V Leiden, but one had the prothrombin variant. We had too
few patients with venous strokes to reach any conclusions about
associations, but other reports have described patients with venous
strokes and factor V Leiden.37 38 39 40 41 42 43 44 45 46 47 In these
series, 11% to 21% of patients with cerebral venous thrombosis have
carried factor V Leiden.40 43 46 More patients
will need to be studied before a conclusion can be reached about a
possible association between the prothrombin variant and venous
stroke.
One potential problem in the current study arises because blood
specimens were obtained at the time of interview. Patients who died or
were disabled as a consequence of their stroke were not
represented among those who were studied. If these
mutations were associated with more severe strokes and consequently
death or disability, we would be underestimating the effect of these
mutations with this study design. We cannot exclude such a possibility
in this study. Eleven patients with ischemic strokes who were
eligible for this study did not participate because of death or
disability. If we assume that all were carriers of the mutations, the
recalculated OR is 3.0 for factor V Leiden and 9.9 for the prothrombin
variant. Such extreme assumptions are unlikely to hold, but these ORs
give an idea of what could be possible.
Other studies that have also been unable to identify an association
between factor V Leiden and stroke have suffered from the same
potential problem because blood samples were collected some time after
the acute event.12 18 33 Nonetheless, in one
study in which blood samples were collected at
presentation, 15 of 348 patients (4.3%) with an
ischemic infarction carried factor V
Leiden.11 In addition, the mutation was not
related to mortality at 1 or 3 months after the initial
stroke.20 In another study in which patients
provided blood within 7 days of their stroke, only 4 of 161 (2.5%)
carried the mutation.27 Whether patients who were
unable to provide consent were excluded from these two studies is
unclear. Finally, in the Physicians' Health
Study,16 209 men for whom blood samples were
available from baseline went on to experience a stroke during
follow-up. Nine of the 209 (4.3%) had the mutation, a figure somewhat
lower than the 6% found in men who remained free of vascular disease.
Although the results of these studies may not entirely apply to women
under 45 years of age with stroke who were enrolled in the current
study, these results suggest that exclusion of women with severe
strokes was unlikely to have had a major effect on our findings.
The current study included too few Hispanic and black patients to
address the question of ethnic or racial variations. In one
study,22 although some Hispanic patients with
ischemic stroke had resistance to activated protein C,
none of the them had factor V Leiden nor did any of the Hispanic
controls. Also of note, factor V Leiden does not seem to play an
important role among black patients with sickle cell disease. Only 1 of
82 such patients (1.2%) had factor V Leiden, and none of the 15 with a
history of stroke had the mutation.32
The current study and others do not support the routine screening for
these mutations in patients with ischemic strokes. Unanswered
by this study is whether screening would be more useful in select
patients, such as those venous strokes. Other investigators have
suggested that such select groups may include patients with an
ischemic stroke combined with one of the following features: a
strong family history of thrombophilia,17
pregnancy and puerperium,15 24
childhood,23 26 an angiographic
complication,31 oral contraceptive use and
antiphospholipid syndrome,22 paradoxical embolus
with deep-vein thrombosis and patent foramen
ovale,29 migraine,13 and
young age without any risk factors.9 10 Given the
relative rarity of such ischemic strokes, the utility of
screening for these two mutations in these settings will remain
difficult to define.
Received October 17, 1997;
revision received December 4, 1997;
accepted December 4, 1997.
© 1998 American Heart Association, Inc.
Original Contributions
Risk of Stroke in Young Women and Two Prothrombotic Mutations: Factor V Leiden and Prothrombin Gene Variant (G20210A)
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—Factor V
Leiden and a prothrombin gene variant, G20210A, are mutations
associated with a thrombotic risk. The aim of our study was to assess
whether these mutations increase the risk of stroke in women under 45
years of age.
Key Words: cerebrovascular disorders • mutation • factor V • prothrombin
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Factor V Leiden and a
recently described variant of the prothrombin gene are both clotting
factor mutations that are associated with an increased tendency for
venous thrombosis.1 2 3 4 Factor V Leiden is a
single-point mutation on the factor V gene in which adenine is
substituted for guanine at nucleotide position 1691. The
mutation results in a change in the factor V molecule where
activated protein C would normally cleave and partially
inactivate factor V. The result is a resistance to
activated protein C.1 2 In a recently
described prothrombin variant, adenine is substituted for guanine at
position 20210 (G20210A) in the noncoding 3' terminal end of the
prothrombin gene.3 4 This variant is associated
with increased prothrombin levels. Although the prothrombin molecule is
normal, its expression is not. Factor V Leiden is a relatively common
hereditary abnormality with a 3% to 5% prevalence of heterozygous
carriers,2 whereas the prothrombin variant, at
1% to 3%, is less prevalent.3 4 Although the
association of these mutations with venous thrombosis has been
demonstrated,1 2 3 4 the association with
arterial disease has not. As recently reviewed, the studies
have not been consistent with respect to an association of
factor V Leiden with coronary artery disease and myocardial
infarction,5 and the studies of the prothrombin
variant are limited.6 Although information on the
prothrombin variant in patients with ischemic stroke is limited
to a single negative report,7 many reports have
concerned factor V Leiden and have not found the risk of
ischemic stroke to be elevated
consistently.8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 Using data collected
as part of a recent population-based case-control
study,35 we examined the association of stroke in
young women with these two mutations.
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
We conducted a population-based case-control study of myocardial
infarction and stroke among women aged 18 to 44 years residing in King,
Pierce, and Snohomish counties, three contiguous counties in western
Washington state. The study was designed to evaluate the risk of
cardiovascular and cerebrovascular diseases with the
use of oral contraceptives.35 Genotyping for
factor V Leiden and the prothrombin variant were performed on a subset
of case patients and control subjects. Associations of myocardial
infarction with factor V Leiden was the focus of one previous
study5 and with the prothrombin variant,
another.6 This report is limited to stroke. As
detailed previously,35 eligible case patients
were free of prior cardiovascular and cerebrovascular
diseases, and diagnosis was made between July 1, 1991, and February 28,
1995, of their first fatal or nonfatal stroke. Stroke was defined by
evidence of new focal neurological deficits lasting more than 24 hours
or resulting in death in less than 24 hours. Strokes were classified as
venous or arterial. Arterial strokes were
further classified as hemorrhagic, ischemic, or other. For a
stroke to be classified as hemorrhagic, imaging studies or lumbar
puncture had to provide evidence of blood in the brain parenchyma, the
subarachnoid space, or both. Arterial dissections
that resulted in stroke were included in the "other" category.
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
In the 106 case patients with blood specimens available for
analyses, 2 strokes were venous and 104 were
arterial (of which 54 were hemorrhagic, 41 were
ischemic, and 9 were dissections). The 1 patient for whom the
factor V Leiden determination was missing had an ischemic
stroke, and the 1 for whom the prothrombin variant determination was
missing had an arterial dissection. The mean age of the 106
case patients was 36.6 years (range, 18 to 44 years), with 88 (83%)
being white, 6 (6%) black, and 12 (11%) classified as other. The mean
age of the 391 control subjects was 37.7 years (range, 19 to 44 years),
with 350 (90%) being white, 9 (2%) black, and 32 (8%) other. Sixteen
of the 388 control subjects (4.1%) but only 1 of the 105 case patients
(0.9%) had the factor V Leiden mutation. The patient was a 33-year-old
white woman with a subarachnoid hemorrhage who had
treated hypertension, diabetes, and obesity. The OR for any stroke was
0.2 (95% CI, 0.03 to 1.7); for hemorrhagic stroke, 0.4 (95% CI, 0.1
to 3.4); and for ischemic stroke, 0 (95% CI, 0 to 2.5). All of
these CIs are broad and include 1.
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Our inability to find a strong association between stroke
and factor V Leiden is consistent with the findings of many
previous studies.18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 We also were unable to
find an association between stroke and the prothrombin variant with
adenine substituted for guanine at position 20210 (G20210A),
consistent with a previous report.7 In
the studies of factor V Leiden, which have included different types of
patients with stroke but almost exclusively ischemic stroke, 0
to 13.8% of patients carried factor V Leiden. In the current study,
none of the 40 women with ischemic strokes had factor V Leiden
(95% CI derived from the binomial distribution, 0 to 8.8%).
Considering prior reports on series of patients with stroke
11 12 13 14 16 18 19 21 22 25 27 28 33 and the results
of this study for ischemic stroke, we calculated that 73 of
1610 stroke patients (4.5%) who have been genotyped carry
factor V Leiden, similar to the 3% to 5% reported for the general
population.2 The association between factor V
Leiden and hemmorrhagic stroke was also not statistically significant
(OR, 0.4; 95% CI, 0.1 to 3.4).
Acknowledgments
This study was supported in part by a contract from the National
Institute for Child Health and Human Development (NO1-HD-1–3107). Dr
Rosendaal is the recipient of a fellowship from the Nederlandse
Organisatie voor Wetenschappelijk Onderzoek (NWO). The authors are
grateful to the many neurologists and other physicians and to the
hospital administrators of medical records, who assisted in the
identification of patients for this study. Fran Chard, Karen Graham,
and Carol Handley-Dahl expertly abstracted medical records; Judy
Kaiser, Marlene Bengeult, Carol Ostergard, Denise Horlander, and Barb
Twaddell recruited and interviewed the patients and control subjects.
Sandy Tronsdal and Jill Ashman supervised these activities. We thank
Esther Vogels, who performed the DNA analyses. Finally, we are
very grateful to all the women who participated in the study.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
A prothrombin polymorphism and
cerebral ischemia in the young. Stroke. 1997;28:1846–1847. Letter.
glutamine mutation.
Stroke. 1996;27:1163–1166.
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